title: Exposure to resveratrol triggers pharmacological correction of fatty acid utilization in human fatty acid oxidation-deficient fibroblasts.
abstract: Carnitine palmitoyl transferase 2 (CPT2) and very-long-chain Acyl-CoA dehydrogenase (VLCAD) deficiencies are among the most common inborn mitochondrial fatty acid β-oxidation (FAO) disorders. Despite advances in their clinical and molecular characterizations, few therapeutic approaches exist for these diseases. Resveratrol (RSV) is a natural polyphenol extensively studied for its potential health benefits. Indeed, it is presently thought that RSV could delay the onset of some cancers, and have protective effects against common aging disorders such as type II diabetes, cardiovascular or neurodegenerative diseases. Here, we show that exposure to RSV induces a dose- and time-dependant increase in FAO flux in human fibroblasts, and can restore normal FAO capacities in a panel of patients' fibroblasts with the mild forms (harboring various genotypes) of CPT2 or VLCAD deficiency. The correction of FAO flux correlated with a marked increase in mutant CPT2 or VLCAD protein level, in cells treated by RSV. Inhibition of sirtuin 1 (SIRT1) by Sirtinol and the use of peroxisome proliferator-activated receptor gamma co-activator-1-alpha (PGC-1α) small interfering RNAs demonstrate that the RSV-induced stimulation of FAO requires the presence of PGC-1α and SIRT1. These results show, for the first time, that RSV markedly induces mitochondrial FAO capacities in human fibroblasts, and provides the initial proof-of-concept that RSV might be efficient for correction of inherited FAO disorders.
authors.affiliation: INSERM U747, Université Paris Descartes, UFR Biomédicale des Saints-Pères, 45, rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Bastin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lopes-Costa
authors.forename: Fatima
authors.initials: F
authors.lastname: Djouadi
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000975:Antioxidants; D005227:Fatty Acids; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013267:Stilbenes; D014157:Transcription Factors; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002334:Carnitine O-Palmitoyltransferase; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D056564:Sirtuin 1; D000077185:Resveratrol